Peritoneal delivery of capsinoids, nonpungent TRPV1 agonists, induces mild hypothermia in conscious mice through TRPV1 activation of visceral vagal afferents

Therapeutic hypothermia (TH) has demonstrated neuroprotection in instances of cardiac arrest and neonatal hypoxia/ischemia but faces different challenges in application to stroke due to the activation of cold defense mechanisms in conscious patients. This study examined the efficacy and specificity of capsinoids (a purified mixture of capsiate and dihydrocapsiate) to induce a sustained fall in core body temperature in conscious mice. Capsinoids function as TRPV1 agonists. However, unlike capsaicin, capsinoids are vulnerable to esterase-mediated breakdown, thus significantly restricting their action to the site of delivery. We showed that capsinoids delivered intraperitoneally (IP) to mice induced a TRPV1-dependent drop in core body temperature into the mild hypothermia range (32-34 °C). Core temperatures dropped without triggering observable cold defense mechanisms (e.g. shivering). The response to capsinoids was dose-dependent and effective in young and aged mice of both sexes. Repeated administration of capsinoids maintained mild hypothermia for up to 6 h, supporting the potential for applying this cooling procedure for promoting post-stroke TH. Capsinoid-induced hypothermia was linked to an activation of heat defense mechanisms, as evidenced by the rapid induction of cutaneous vasodilation and subsequent drop in core body temperature. We showed that IP capsinoids activate vagal afferents, as demonstrated by an increase in c-Fos positive neurons in the nodose ganglion. Finally, we provide proof-of-principle showing that capsinoid-induced hypothermia is neuroprotective in an experimental model of ischemic stroke.